A specific gene for increased risk of breast and ovarian cancer, BRCA1, was recently found on chromosome 17q. In this project we are working on characterizing BRCA1 using data from an international genetic epidemiologic study of premenopausal bilateral breast cancer. These data consist of information on families whose index case (i.e.,proband) was ascertained from cancer registries in Connecticut and Los Angeles, and from major hospitals (that covered 95% of breast cancer cases) in Montreal and Quebec. A total of 460 probands were identified who were still living and who had premenopausal bilateral breast cancer. We have extensive data on these families, DNA on 452 individuals from 68 families that were potentially informative for linkage, and, 236 formalin-fixed, paraffin-embedded tissue blocks from 101 cases. We have data on HER-2 and on p53 and 17q haplotypes. Pertinent results to date suggest 1) that a substantial proportion of our families involve BRCA1; 2)that synchronicity is a source of heterogeneity; 3) that BRCA1 may interact with HER-2 and p53; and 4) that BRCA1 may interact with the use of oral contraceptives. Current work includes sequencing BRCA1 for the 68 probands of these families, and then, when sequence variations are detected in the proband, undertaking more directed analyses in the remaining family members to determine mutation status. We will also conduct protein-based analyses to characterize BRCA1.